Clinical Investigation
Phase I Trial of Pelvic Nodal Dose Escalation With Hypofractionated IMRT for High-Risk Prostate Cancer

Presented at the 2010 American Radium Society Annual Meeting, Cancun, Mexico, May 5, 2010.
https://doi.org/10.1016/j.ijrobp.2010.09.018Get rights and content

Purpose

Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5½ weeks.

Methods and Materials

Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months.

Results

The median follow-up time was 25.4 months (range, 4.2–57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose–volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only.

Conclusions

Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients.

Introduction

The clinical benefit of pelvic nodal irradiation for prostate cancer has been difficult to establish and is uncertain. Although progression-free survival benefit has been reported in Radiation Therapy Oncology Group (RTOG) 94-13 at 5-year follow-up (1), updates of this study (2) and of other trials 3, 4 have either shown only trends or failed to demonstrate benefit using doses of 45–50.4 Gy. Salvage radiation data indicate improved biochemical control with increasing doses to the 66- to 70-Gy range when targeting microscopic disease in the prostatic fossa 5, 6, but prescribed pelvic nodal doses have been limited by toxicity concerns. Beyond well-known difficulties in reliably selecting patients at high risk for nodal involvement, one hypothesis for such uncertain benefit from pelvic radiotherapy is that contemporary doses from 45 to 50.4 Gy are suboptimal for controlling microscopic disease.

Advances and techniques such as intensity modulated radiation therapy (IMRT), bowel displacement techniques (7), and bladder filling can better facilitate limiting the dose to the small bowel while treating pelvic nodal basins. When using conventional fractionation for the pelvic nodes and the prostate, two separate three-dimensional conformal or IMRT plans must be generated; however, one IMRT plan may direct the entire treatment if hypofractionated radiotherapy is delivered to the prostate gland via a simultaneous integrated boost. Early evidence also suggests that hypofractionated radiotherapy may confer some additional advantage by increasing the therapeutic ratio because of a hypothesized low α/β ratio for prostate cancer (8).

We therefore tested whether image-guided IMRT can safely deliver escalated nodal doses while treating the prostate simultaneously with a hypofractionated schedule. We present a dose–volume analysis of toxicities and preliminary biochemical control estimates in 53 high pelvic nodal risk patients treated to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 2.5-Gy fractions, with the entire treatment delivered in 28 fractions.

Section snippets

Methods and Materials

Patients with high-risk prostate adenocarcinoma with prediction of ≥10% pelvic lymph node involvement (9) were eligible for treatment on this Phase I prospective protocol, approved by the institutional review board of the University of Wisconsin Hospital. In addition, any patient with radiographic evidence of pelvic lymph node involvement but absence of distal metastases could be enrolled in the protocol. No patient had evidence of distal metastases on bone scan and computed tomography (CT) of

Results

Between August 2004 and September 2008, a total of 53 patients were treated. Fifty patients received ADT for a median duration of 12 months (range 3–28 months), with 3 patients not so treated because of patient refusal. Patient characteristics are detailed in Table 1. The dosimetric parameters achieved using IMRT to spare organs at risk are detailed in Table 2. The median follow-up time was 25.4 months (range, 4.2–57.2 months).

Discussion

Pelvic nodal irradiation, delivered with various schedules of ADT, has been the historic standard for locally advanced prostate cancer 13, 14, 15, 16. The two minimum requirements for clinical benefit from pelvic radiotherapy are the selection of patients at sufficiently high risk for nodal metastatic involvement and the safe delivery of radiation doses sufficiently high to sterilize nodal metastases.

Several models have estimated the risk of pelvic nodal involvement 17, 18, 19, 20, 21, many of

Conclusion

Pelvic nodal IMRT dose escalation to 56 Gy delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in 28 fractions over 5½ weeks is a resource- efficient, convenient, and well-tolerated regimen that produces acceptable preliminary biochemical control rates. No in-field pelvic nodal failures have been observed to date despite two periaortic failures outside the treatment volume. Although the benefits of pelvic nodal irradiation using conventional 45- to 50.4-Gy doses remain

References (35)

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Supported by NCI Grant R01CA106835.

Conflict of interest: none.

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